The main objective of these studies is to determine if cognitive neurorehabilitation improves memory and induces neural plasticity in residual brain areas following stroke. There is a well-established model system to examine rehabilitation-induced motor recovery and plasticity following experimental strokes in rats. Motor recovery is thought to be a process of "relearning" in which motor functions are reacquired through functional compensation within spared brain regions. Several laboratories have demonstrated that such functional compensation is supported by synaptic plasticity within residual neural circuits that is driven by rehabilitation. However, it is unknown whether cognitive neurorehabilitative training will improve cognitive performance, such as improved memory. It seems possible that focused cognitive neurorehabilitation would improve specific areas of cognitive function and induce greater neural adaptive changes in spared brain regions that are relevant to the rehabilitated cognitive function. However, basic neurobiology research suggests that the neural basis of motor skills acquisition and performance is different from cognitive tasks such as episodic memory. Motor skills and cognitive functions involve different neural networks and thus the requirements of learning- induced neural plasticity in these networks are also likely different. This proposal is to systematically investigate how cognitive rehabilitative therapy after ischemic insult can improve cognitive ability, including the neural bases of the improvements and the efficacy of combining rehabilitation with pharmacological treatments. This will be investigated in a rat model of stroke (middle cerebral artery occlusion) using a combination of sensitive behavioral measures and manipulations of cognitive function and assays of neuronal and synaptic structural plasticity in the hippocampus. The aims of this project are to test the hypotheses that: 1) Post-stroke training in tasks requiring episodic memory will improve performance on tests of cognitive ability in an animal model of stroke compared to non- trained groups;2) Cognitive rehabilitative training that improves cognitive ability following stroke will result in restorative plasticity in the hippocampus compared to non-trained groups;3) Coupling cognitive neurorehabilitative training with an acetylcholinesterase inhibitor will enhance the efficacy of post-stroke cognitive neurorehabilitation. These investigations are expected to elucidate mechanisms involved in cognitive recovery after brain injury, with the potential of leading to better clinical treatment approaches. PUBLIC HEALTH RELEVANCE: Currently, there is not a well-developed rodent model of cognitive neurorehabilitation following neurological insult. We propose to develop a rat model of cognitive neurorehabilitative training that will provide knowledge regarding the effectiveness of task specific cognitive training and the neural mechanisms underlying its therapeutic efficacy following stroke. These investigations will serve as a foundation to test adjunctive therapies to optimize recovery from stroke.